The aorta is an integral part of the cardiovascular system and should not be considered as just a conduit for blood supply from the heart to the

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2 The aorta is an integral part of the cardiovascular system and should not be considered as just a conduit for blood supply from the heart to the limbs and major organs. A range of important pathologies affect the aorta and are responsible for a high level of morbidity and mortality in affected patients. Many of these conditions are seen in the adult congenital population, especially as advances in diagnosis and treatment mean these patients are surviving well into adulthood. As we gain a greater understanding of these disorders, especially the underlying genetics and pathophysiology, it becomes clear that the aorta is a highly complex part of the vascular tree. As such, the aorta requires increasingly sophisticated imaging techniques for the diagnosis, treatment and follow-up of these patients. The advantages and disadvantages of the various imaging techniques available to clinicians will be discussed in the context of both acute and chronic aortic pathology.

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4 Endothelial Dysfunction in Atherosclerosis endothelial cells in early atherosclerosis begin to express molecules on their luminal surface in response to the presence of lipid in the vessel wall. These molecules are of the selectin (P- and E-) and adhesion classes Ross R. N Engl J Med 1999; 340:

5 proinflammatory cytokines including interleukin-1, monocyte chemotactic protein-1, and tumor necrosis factorenzymes capable of directly digesting the fibrous cap of the plaque, including several members of the matrix metalloproteinase (MMP) family

6 Plaque macrophages have a high rate of apoptosis and along with the accumulated lipid they constitute the lipid core of the plaque A balance is established between the proinflammatory actions of macrophages& infiltrating lymphocytes &the protective layer of smooth muscle cells separating the lipid core from the vessel lumen Ross R. N Engl J Med 1999; 340:

7 Where the degree of inflammation is sufficient, the fibrous cap can rupture, exposing the thrombogenic lipid core to the bloodstream This may cause a local arterial thrombosis from which clinical events such as myocardial infarction can result Ross R. N Engl J Med 1999; 340:

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10 : RI <1 RI >1

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12 Intense aortic uptake due to inflammation (unstable plaque formation). A unique example of an inflammatory condition is the one caused by the atherosclerotic plaque formation that is associated with an abundance of macrophages known by it s avidity to 18F-FDG The degree of uptake is usually less than the uptake within the neoplastic tissues. However, there is clearly an overlap between the 2 conditions and, in some cases, the uptake could even exceed the neoplastic uptake

13 Aorta imaging with PET/CT. The left image is a noncontrast coronal CT image showing calcification of the abdominal aorta (group of 3 green arrows). The center and right images are coregistered PET and fused PET/CT images, respectively, demonstrating significant FDG uptake within the ascending aorta (single arrow) but relatively less FDG uptake in the calcified abdominal aorta. The green cross is in the inferior vena cava, where there is low FDG uptake.

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15 Techniques for imaging the unstable plaque. This scheme illustrates morphological and biological tools for visualizing vulnerable plaques. Modalities with clinical applications are given in bold.

16 Illustration of the relative spatial resolution of common imaging techniques (top), along with their sensitivity values (bottom).

17 Christian M. Matter, Matthias Stuber, and Matthias Nahrendorf (European Heart Journal (2009) 30, )

18 Lipoproteins methylated and oxidized lipoproteins, and antibodies recognizing oxidized low-density lipoprotein Markers of inflammation: upregulated integrin expression, endothelin receptors, IgG, chemoattractant peptide expression, macrophage, macrophage function, and extradomain B of fibronectin Markers of cell death (e.g., especially of macrophages and smooth muscle cells, which can be identified with annexin V Antibodie s recognizing a change in the smooth muscle phenotype

19 Antibody Z2D3, is a chimeric antibody generated against homogenized human atherosclerotic plaques, capable to identifies an antigen expressed exclusively by the psmcs in the atherosclerotic lesions Gamma imaging studies with Z2D3 in experimental models of atherosclerosis have demonstrated Z2D3 uptake in intimal lesions with proliferating SMCs

20 Targeting Proliferating Smooth Muscle Cells in Experimental Atherosclerotic Lesions, Rabbit Aorta CONTROL ATHEROSCLEROTIC PATH Z2D3, Human Coronary IN VIVO MACRO EX VIVOAUTORG Z2D3, Rabbit Aorta

21 L. Johnson

22 J Nucl Cardiol 1998 Plaque Immuno staining Z2D3 SPECT Coronal View Angio Transverse View

23 99m Tc-AP4A Imaging for psmc in Atherosclerotic Lesions Injection 3 Hours Ex-Vivo Elmaleh, Narula 2001

24 SUDAN IV AUTORADIOGRAPHY I- 125-MDA2 OXIDIZED LDL IMAGING RADIOLABELED MDA2, AN OXIDATION-SPECIFIC, MONOCLONAL ANTIBODY Rationale: Oxidized-LDL are present only in the atherosclerotic lesions but not in the normal arteries and play a crucial role in the pathogenesis and adverse consequences of the atherosclerotic lesions. Tsimikas et al. JNC 1999

25 OXIDIZED LDL IMAGING RADIOLABELED MDA2, AN OXIDATION-SPECIFIC, MONOCLONAL ANTIBODY Tc99m-MDA2 In Vivo imaging Ex Vivo (Sudan IV) Control Rabbit Experimental Rabbit Atherosclerotic Lesions Tsimikas et al. JNC 1999

26 111 In-Coproporphyrin Imaging for Experimental Atherosclerotic Injection 3 Hours Lesions Injection 3 Hours Ex-Vivo Control Atherosclerotic C A Jain, Narula JACC 2000

27 To address a need for harmonization of scan parameters of the ideal circulation time of 18F-FDG, we scanned patients with atherosclerotic abdominal aortic aneurysms. They performed PET/CT at 45, 60, 120, and 180 min after an injection of 18F-FDG. They investigated whether there were 18F-FDG uptake differences with time in the aortic wall and lumen of the aneurysms to determine the optimal time to image vascular inflammation using 18F-FDG PET/CT. Leon J. Menezes, Carl W. Kotze, Brian F. Hutton, Raymondo Endozo, John C. Dickson, Ian Cullum, Syed W. Yusuf, Peter J. Ell, and Ashley M. Groves (J Nucl Med 2009; 50: )

28 Fused axial PET/CT of ROIs applied to aortic aneurysmal wall and lumen at mid-point of dynamic acquisitions at 45 (A), 60 (B), 120 (C), and 180 min (D) after injection of 18F-FDG.

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30 Aorta imaging with PET/CT. The left image is a noncontrast coronal CT image showing calcification of the abdominal aorta (group of 3 green arrows). The center and right images are coregistered PET and fused PET/CT images, respectively, demonstrating significant FDG uptake within the ascending aorta (single arrow) but relatively less FDG uptake in the calcified abdominal aorta. The green cross is in the inferior vena cava, where there is low FDG uptake.

31 IMPORTANT NOTES FDG PET imaging showed that the presence of inflammation in one arterial territory is highly predictive of inflammation in others. This finding suggests a form of systemic arterial activation. Supporting this theory of systemic activation, it has been found that the degree of arterial FDG uptake was associated with blood levels of several systemic inflammatory biomarkers, including those from the MMP family, and strong trends among both the interleukin group and CRP, but not with LDL One particular advantage of FDG PET atheroma imaging over measurement of circulating biomarkers is the ability to pinpoint a particular arterial segment as being inflamed, allowing it to be targeted for treatment

32 a, b: FDG-PET images demonstrate abnormal FDG accumulation in the aortic arch. Moderate diffuse uptake is seen in the stomach (arrowhead). No other abnormal FDG uptake is seen. c, d: CT images show a dilated thoracic aorta with wall thickening. FDG-PET demonstrates intense uptake corresponding to the aneurysmal wall. (c, contrast-enhanced CT; d, FDG-PET axial views corresponding to the CT images.)

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34 Focal increase d FDG in relation to calc

35 PET/CT image of aorta before (top) and during (bottom) antiatherosclerosis therapy. Note reduction in FDG uptake in the aortic wall

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39 Blood Pool Activity [SUVmean blood pool]) largest luminal area possible not containing the aortic wall or dissection membrane Aortic Wall Activity SUVmax The diagnosis of an AD was made in the case of an intimal dissection membrane separating the true and false aortic lumens The diagnostic criteria of an intramural hematoma included semicircular or circular aortic wall thickening without intimal disruption exceeding 5 mm A ROI corresponding to the highest 18F- FDG uptake in the dissection membrane or the adjacent vessel wall SUV Ratio. Aortic SUVmax. SUVmean blood pool

40 Images of 37-y-old man with acute type B dissection of aorta: sagittal (A) and coronal (C) PET/CT images and the corresponding sagittal (B) and coronal (D) nonfused CT images.

41 It has been found that acute dissection of the aortic wall leads to elevated metabolic activity in of the aortic wall (due to accumulation of glycolytic active cells such as macrophages and activated myofibrinocytes in the vessel wal), whereas show increased 18F- FDG uptake. In contrast to chronic stable AD, patients with acute intramural hematoma and secondary progressive chronic AD showed also elevated glucose metabolism in the aortic vessel wall Therefore, increased 18F-FDG uptake in the aortic wall seems to correlate with acute injury and its repair, and 18F-FDG PET/CT.

42 Images of 65-y-old woman with acute intramural hematoma: coronal (A) and sagittal (D) PET images, coronal (B) and sagittal (E) CT images, and coronal (C) and axial (F) PET/CT images

43 Images of 65-y-old man with chronic, stable dissection of aorta: coronal PET (A), fused PET/CT (B), and CT (C) images. No specific 18F-FDG uptake is detected

44 Integrated systems that combine an imaging modality with high spatial resolution (MRI or CT) with one with high sensitivity (PET or SPECT) should help to overcome limitations in aortic diseases assessment. Finally, molecular imaging has already spurred the development of platforms that can transport contrast moieties to specific biological targets in atherosclerotic plaque. In the future, these platforms could also simultaneously permit delivery of therapeutic agents to plaques with minimal systemic toxicity.